Nociception is the sensory process that allows animals to detect and avoid potentially harmful stimuli. This escape response appears universal in metazoans, being observed in non-mammalian and mammalian vertebrates including humans, also in invertebrates such as nematodes and fruit flies. Drosophila has emerged as a powerful system to study the genetics of nociception, due largely to the development of several pain administration and avoidance paradigms. Hazardous stimuli known to trigger nociception sensory transduction include noxious heat, noxious chemicals, UV-irradiation, and harsh mechanical stress. Drosophila has also emerged as an excellent system to study the cellular and genetic bases of hematopoiesis, including immune cell induction. Blood cell formation is a conserved developmental process and several parallels exist between hematopoiesis in this model organism and humans. The discovery of a stem cell-like hematopoietic progenitor niche in Drosophila represents a highly-significant contribution of this model system to the study of stem cell biology. Compelling data exist to support the belief that the posterior signaling center (PSC) functions as the niche within the larval lymph gland, with this domain essential for maintaining normal blood cell homeostasis. Communication between the PSC and prohemocytes present in the lymph gland medullary zone is crucial for controlling the decision as to maintaining a pluri-potent state versus initiating a hemocyte differentiation program. Such lymph gland cellular organization and molecular signaling is remarkably similar to that observed in the hematopoietic stem cell niches of several mammals. What brings together the vital processes of nociception and immune cell production is our recent discovery that mechanical stress administered to Drosophila larvae results in a robust induction of hemocyte differentiation within the lymph gland hematopoietic organ. This striking change in blood cell homeostasis includes the prodigious production of lamellocytes, cells normally induced as a protective cellular immune response to wasp pathogen introduction into a larval host. It is noteworthy that our preliminary findings suggest that lamellocyte induction occurs via different mechanisms in response to mechanical stress administration versus parasitic wasp infestation. Two Specific Aims are proposed to better comprehend the nature of mechanical stress induction of this cellular immune response. We plan to (1) investigate if genes known to function in pain avoidance behavior are also required for the cellular immune response to larval mechanical stress, and (2) identify the signaling pathway(s) regulating the cellular immune response to animal mechanical stress. Together, these approaches will allow for the use of Drosophila as a valuable model to investigate the evolutionarily conserved genetics of pain sensing and avoidance, while also addressing mechanisms controlling immune cell induction due to stress exposure.